ADHATODA VASICA1

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ADHATODA VASICA: VASAKA

Adhatoda vasica is a well-known plant drug in Ayurvedic and Unani medicine. Adhatoda leaves have been

used extensively in Ayurvedic Medicine primarily for respiratory disorders. The medicinal properties of

Adhatoda vasica, called Vasa or Vasaka in Sanskrit have been known in India and several other countries

for thousands of years.

DESCRIPTION

Macroscopic-Leaves, 10-30 cm long and 3-10 cm broad, lanceolate to ovate-lanceolate, slightly

acuminate, base tapering, petiolate; petioles 2-8 cm long, exstipulite, glabrescent, 8-10 pairs of lateral vein

bearing few hairs; dried leaves dull brown above, light greyish brown below; odour, characteristic; taste,

bitter.

Microscopic-Transverse section of leaf shows, dorsiventral surface with 2 layers of palisade cells; in

surface with 2 layers of palisade cells; in surface view, epidermal cells sinuous with anomocytic stomata on

both surfaces, more numerous on the lower; clothing trichomes few, 1-3 rarely upto 5 celled, thin-walled,

uniseriate, upto 500 and glandular trichomes with unicellular stalk and 4 celled head measuring, 25-36 in diameter in surface view; cystoliths in mesophyll 1 years, elongated and cigar shaped; acicular and

prismatic forms of calcium oxalate crystals present in mesophyll; palisade ratio, 5-6, 5-8.5; stomatal index,

10.8-14.2-18.1 for lower surface.

ORIGIN AND DISTRIBUTION

The plant is distributed all over the plains of India & in lower Himalayan ranges, ascending to a height of

1,500 m.

TRADITIONAL MEDICINAL USES

Adhatoda vasica Nees (Vasaka) is used in various chest affections and enjoys wide reputation as an

expectorant in the indigenous system of medicine. it was used also by traditional midwives at the time of

delivery. The leaves, the roots and flowers of Adhatoda vasica are extensively used in indigenous medicine

as remedy for cold, cough, bronchitis and asthma. Both the decoctions and powder from constituents ofmany preparations use din the Ayurvedic medicine for various affections of the respiratory tract. In chronic

bronchitis and asthma it is said to be very useful. The medicine was considered so useful in tuberculosis

that it was said that no man suffering form this disease need despair as long a vasica plant exists in this

world. The juice of the leaves is used in diarrhoea and dysentery and powdered leaves in malaria in

southern India.

Adhatoda vasica is traditionally used in many of the following ways:

Juice from the leaves and the decoction of the leaves and roots are helpful in asthma, bronchitis andchronic coughs and breathlessness.

Used for bleeding due to idiopathic thrombocytopenic purpura, local bleeding due to peptic ulcer, piles,menorrhagia.

Relief in pyorrhoea and for bleeding gums by locally application.

Relieves or eases muscular spasms, cramps or convulsions Stimulates contraction of the uterine muscle, facilitating or speeding up childbirth

Lowers blood pressure

Adhatoda is said to be non-poisonous to mammals, but to kill fish, insects, and lower organisms.


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CHEMICAL CONSTITUENTS

The leaves of the plant contain an essential oil and alkaloids vasicine, N-oxides of vasicine, vasicinone,

deoxyvasicine and maiontone. The roots are known to contain vasicinolone, vasicol, peganine and 2' -

hydroxy - 4 - glucosyl -oxychalcone. The flowers contain -sitosterol-D-glucoside, kaempferol, itsglycosides and quereetin.

Vasicine OH

N

N

PHARMACOLOGICAL ACTIVIES AND CLINICAL TRAILS

Abortifacient activity

A survey programme was organised in Lucknow and Farrukhabad, two towns of Uttar Pradesh, from

March 1987 to July 1987. During the survey, the common folk medicine plants used by women were

recorded and Ayurvedic and Unani drug encyclopedias were consulted for the antireproductive potential of

these plants. Aqueous or 90% ethanol extracts of the plants of interest were studied in rats orally dosed for

10 days after insemination with special reference to effects on fotel development. Leaf extracts of Moringa

oleifera and Adhatoda vasica were 100% abortive at doses equivalent to 175 mg/kg of starting dry material.

Anti-allergic activity

A methanolic extract from the entire plant has been shown to possess anti-allergic activities in the guinea-

pig after inhalation or intragastric administration at doses of 6 mg per animal or 2.5 gm/kg, respectively.

Compound 73/602 (AA) is a structural analogue of vasicinone, an alkaloid present in the leaves and rootsof Adhatoda vasica (Acanthaceae). It possesses potent antiallergic activity in mice, rats and guinea pigs.

The pK (a) of AA was determined to be 2.87 +/-0.19 by UV spectrophotometry. The absorption kinetics of

this compound was studied in-situ using a rat gut technique at pH 2.6 and 7.4. The rate of absorption at pH

2.6 (0.0288 +/- 0.004 min (-1)). This characteristic behavior was attributed to the low pK (a) of AA, weekly

basic compounds, where nearly 35% of the compound remained in the unionized form at pH 2.6. Also, the

return of compound into the mucosal lumen from the blood capillaries over a period of 2 h after

administering a 2 mg dose in tail vein was less than 0.3%. Hence it was concluded that entero-enteric

circulation of AA did not contribute significantly to the in-situ absorption rates. Pharmacokinetic

parameters of AA were determined in male rats after administering a single 10 mg/kg intravenous dose

(i.v.) and 50 mg/kg oral bolus dose. Following i.v. administration the initial decline in serum concentration

was rapid with half-life of 20.2 min. after a single oral dose the concentration-time data of AA in rats was

50.6 min, indicating absorption rate limiting disposition at the high dose given. Comparison of ACU of oral

and i.v. data indicates that only about 60% of the oral dose reaches the systemic circulation.

Structure-activity relationships obtained from in vitro screening results obviously indicate that the highest

inhibition effects on cyclooxygenase and 5-lipoxygenase are found amongst the class of phenolic

compounds (flavonoids, polyphenols, coumestans, phenol carboxylic acids) and arachidonic acid analogous

(alkylamides, retinoids, arylheptanoids, thiosulfinates, sulfinyl disulfides). The antiinflammatory activities

of some triterpenenic acids, sesquiterpene lactones and polysaccharides may be due to their

immunomodulating activities on the complement and/or T-lymphocyte populations, respectively. in the

search for potential antiallergic and antiasthmatic compounds, the thiosulfinates of onion were found to be

active principles of the drug. The mechanism of action of some other antiallergic plant drugs (i.e.

Tylophora asthmatica, Adhatoda vasica, etc.) has not yet been clarified.


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Anti-asthmatic activity

A methanolic extract from the entire plant has been shown to possess anti-asthmatic activities in the

guinea-pig after inhalation or intragastric administration at doses of 6 mg per animal or 2.5 gm/kg,

respectively.

Hitherto unknown alkaolids from Adhatoda vasica showed pronounced against allergen-induced bronchial

obstruction in guinea pigs (10 mg/ml aerosol). Androsin from picrohiza kurroa prevented allergen- and

PAF-induced bronchial obstruction (10 mg/kg orally; 0.5 mg inhalative). Histamine release in vitro was

inhibited by other compounds of the plant extract yet to be identified. Pharmacological effects of plant

extracts and pure compounds in man are under investigation.

Anti-inflammatory activity

Adhatoda vasica Nees is a shrub widespread throughout the tropical regions of Southeast Asia. It possesses

a wide spectrum of medicinal properties including positive effects on inflammatory diseases. The

antiinflammatory activity of the methanol extract, the non-alkaloid fraction the saponins and the alkaloids

was evaluated by the modified hen's egg chorioallantoic membrane test. The alkaloid fraction showed

potent activity at a dose of 50 microg/pellet equivalent to that of hydrocortisone while the MeOH extract

and the other fractions showed less activity.

Anti-microbial activity

The present report deals with the preliminary experiments designed to evaluate the in vitro effects ofAdhatoda vasika (ARDUSI) leaf (AVL) extract on micro-organisms of inflamed gingiva by employing

antibiotic sensitivity test by disc diffusion method. In vitro sensitivity test with AVL extract of micro-

organism of inflamed gingival showed significant antimicrobial activity.

Anti-tubercular activity

The oil obtained from leaves flowers and roots of vasica plant possesses significantly high activity against

tubercle bacilli. The growth of M.tuberculosis B 19-4 (human) is inhibited in a concentration of 2 g.; that

of B 19-3 (bovine) partially in a concentration of 2 g./c.c., and completely in a concentration of 5g;

while of B19-1 (avian) strain is inhibited completely in a concentration of 5 g. the anti-tubercular activityof the active principle form leaves is twice less than that of streptomycin. The action of the active principle

is specific fro tubercle bacillus. The growth of non-acidfast bacteria is not inhibited in a concentration of

500 g./c.c. The drug in a dose of 2.3g/kilo body-weight when injected subcutaneously to mice dose not

produces any toxic symptoms. Five hundred mg./kilo injected subcutaneously in guinea-pig does notproduce any toxic symptoms. The oil has low toxity for paramecia. 1/5,000 dilution of the oil does not kill

these in one hour.

Anti-tussive activity

The antitussive activity of Adhatoda vasica (AV) extract was evaluated in anaesthetized guinea pigs and

rabbits and in unanaesthetized guinea pigs. AV was shown to have a good antitussive activity.

Intravenously, it was 1/20-1/40 as active as codeine on mechanically and electrically induced coughing in

rabbits and guinea-pigs. After oral administration to the guinea-pig the antitussive activity of AV was

similar to codeine against coughing induced by irritant aerosols.

Bronchodilatory activity

The pharmacological actions of vasicinone on the bronchial musculature were studied on the guinea pig

tracheal chain, on perfused guinea-pig lung and by the overflow method in intact guinea pigs. Vasicinonehad a definite bronchodilator action on the normal lungs and a powerful bronchodilator action against the

histamine-induced bronchoconstriction; but its action was weaker than adrenaline. Laevo-vasieinone was

howevere, stronger in action than its DL-from. Vasicinone showed a slight and transient fall in the blood

pressure of a dog. On isolated perfused hearts of guinea pig and rabbit vasicinone had a positive inotropic

action and increased the flow in the coronary vessels. Both L-and DL-forms of vasicine displayed a

brochoconstrictor action, had a negative inotropic action on the heart and also reduced the flow in the

coronary vessels.


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Chemopreventive efficacy

The effect of two different doses (50 and 100 mg/kg body wt/day for 14 days) of 80% ethanolic extract of

the leaves of Adhatoda vasica were examined on drug metabolizing phase 1 and phase 11 enzymes,

antioxidant enzymes, glutathione content, lactate dehydrogenase and lipid peroxidation in the liver of 8

weeks old Swiss albino mice. The modulatory effect of the extract was also examined on extra-hepatic

organs viz. lung, kidney and forestomach for the activities of glutathione S-transferase, DT-diaphorase,

superoxide dismutase and catalase. Significant increase in the activities of acid soluble sulfhydryl (-SH)

content, cytochrome P450, NADPH-cytochrome P450 reductase, cytochrome b5, NADH-cytochrome b5

reductase, glutathione S-transferase (GST), DT-diaphorase (DTD), superoxide dismutase (SOD), catalase

(CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) were observed in the liver at both

dose levels of treatments. Adhatoda vasica acted as bifunctional inducer since it induce both phase 1and

phase 11 enzyme systems. Both the treated groups showed significant decrease in malondialdehyde (MDA)

formation in liver, suggesting its role in protection against prooxidant induced membrane damage. The

cytosolic protein was significantly inhibited at both the dose levels of treatment indicating the possibility of

its involvement in the inhibition of protein synthesis. BHA has significantly induced the activities of GR

and GSH in the present study. The extract was effective in the present study. The extract was effective in

inducing GST and DTD in lung and forestomach and SOD and CAT in kidney. Thus, besides liver other

organs viz., lung, kidney. Thus and forestomach were also stimulated by Adhatoda, to increase the potential

of the machinery associated with the detoxification of xenobiotic compounds. But, liver and lung showed a

more consistent induction. Since the study of induction of the phase 1 and phase 11 enzymes is considered

to be a reliable marker for evaluating the chemopreventive efficacy of particular compound these findingsare suggestive of the possible chemopreventive role played by Adhatoda leaf extract.

Hypoglycaemic activity

Ethanolic extracts from the leaves showed hypoglycaemic activity after oral administration in rats and

rabbits.

Muscle relaxant activity

An essential oil from the leaves of vasica showed smooth muscle relaxant activity in the isolated guinea-pig

tracheal chain.

Thrombopoletic activityRepeated oral and intramuscular administration of vasicine (an alkaloid from Adhatoda vasica) resulted in

an increase in platelet count in normal rats, mice, rabbits and dogs. This increase in platelets was alsoassociated with significant hyperplasia of megakaryocytes in the bone marrow. No effects were observed

on haemoglobin level and RBC or WBC counts and morphology. Bleeding and clotting times were not

significantly altered nor was there any evidence of in vitro haemolysis. Vasicine did not influence platelet

function. Results control of capillary haemorrhages and for correction of drug induced bone marrow

depression.

Uterotonic activity

The uterotonic activity of vasicine was investigated in details on the uteri of different species of animals

and in different hormonal states both in vitro and in vivo. Its uterotonic activity was found to be similar to

that of oxytocin and methyl ergometrine. It was observed that the uterotonic activity of vasicine was

influenced by the degree of priming of the uterus by oestrogens (known to enhance the synthesis of

prostaglandins in the uterus) and it was markedly reduced after pretreatment of the uterus with aspirin and

indomethacin. This indicated that the uterotonic effect of vasicine was atleast partly medicated through therelease of prostaglandins.

PHARMCOKINETICS

Vasicine, 20 mg/kg body weight, given intramuscularly was well absorbed reaching a maximum

concentration of about 50 g/ml in blood in both pregnant and non-pregnant rats and about 10 g/ml inamniotic fluid. After intravenous injection in rats and mice high concentrations of vasicine were found in

the uterus within 5 min and the peak level was achieved after 10 min. the half-life was 5-7 min, 1.5 and 2 h

after intravenous, intramuscular and subcutaneous administration, respectively. the studies on absorption

and distribution of vasicine in mice after intravenous, intramuscular and subcutaneous administration show

similar results as those reported in rats. After oral administration very low concentrations were found in the

uterus. Vasicine is metabolized in the liver to vasicinone and other metabolites which contribute to the firs

pass effect and which is an important way of elimination of vasicine.


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It is reported that vasicine and its metabolites are mainly excreted in the urine. On intravenous and

intramuscular administration about 55% of the excreted product in the first 18 to 22 h, respectively, was

vasicine, while on oral administration about 18% of the excreted product was vasicine during the first 24 h.

TOXICOLOGY

All studies on the effects of A. vasica extract and vasicine on the reproduction system and function are

reviewed under reproduction toxicity even though they were not always assigned as toxicity studies.

General toxicology

The acute toxicity of vasicine after single administration is moderate. A similar degree of acute toxicity has

been found by other investigators and in other species.

Vasicine was given daily for 2 weeks to groups or rats (six males and six females in each) subcutaneously,

10, 25 and 50 mg/kg body weight and orally, 20 and 100 mg/kg body weight. A control group was treated

with normal saline. Groups of dogs (two males and two females in each) were treated subcutaneously, 3.5

and 17.5 mg/kg body weight and orally 35 mg/kg body weight. A fourth groups severed as control. Clinical

observations, clinical chemistry and histopathological examination of major organs were performed on all

the animals. No remarkable adverse effects were recorded in any species.

The general toxicity after repeated oral administration of vasicine daily for 6 months has been studied inrats and monkeys. Four groups of rats (ten males and ten females in each) were given 1, 2.5, 5 and 10

mg/kg body weight respectively. Clinical observations, clinical chemistry and histopathology of the major

organs were performed in both the species. Mortality rate and body weight of the treated animals were

comparable with the controls except the mortality rate in the treated male rats which was dose dependently

increased. Haematological and biochemical determinations were within the normal physiological range.

Autopsy and histopatological examination of major organs did not reveal any abnormalities.

Reproduction toxicity

The observation of the uterotonic action of vasicine prompted the testing of vasicine for its abortifacient

activity. Mated female rats (ten in each group), were given vasicine, 5-15 mg/kg body weight

intraperitoneally on day 8 or 16 of gestation. No effects on implantation or delivery were found.

Pretreatment with estradiol did not change the outcome of the vasicine treatment. In guinea pigs vasicine,

30 mg/kg body weight given intraperitoneally caused abortion in four out of eight animals in latepregnancy. Pretreatment with estradiol increased the effect of vasicine.

In rats vasicine, 5 and 10 mg/kg body weight was administered intraperitoneally to groups of ten animals

at various intervals of pregnancy. No anti-implantation effect (no effect when given on day 1-7) but an

abortifacient effect, pregnancy failure after day 7 which increased during pregnancy was found.

A pregnancy failure or abortifacient activity was also observed in hamsters (ten in each group) receiving

vasicine 2.5 and 5 mg/kg body weight, intraperitoneally on day 7-9 and day 10-12 of pregnancy or in

guinea pigs (in groups of three to ten animals) receiving vasicine 5 and 10 mg/kg body weight

intraperitoneally for 3 days at different stages of pregnancy.

In rabbits, vasicine 2.5, 5 and 10 mg/kg body weight was administered intraperitoneally or intramuscularly,

or 20 mg/kg body weight was administered orally day 10-12, day 17-19 or day 22-24 or pregnancy togroups of two to four animals. There were no control groups of two to four animals. There were no control

groups. The animals were observed daily for any vaginal bleeding or expulsion of conspectuses.

Abortificient activity was observed in more than half of the animals after parenteral administration while no

activity was observed after oral administration.

Teratogenic studies on vasicine were performed in rats and rabbits. Groups of mated rats were given

vasicine, 2.5, 5 and 10 mg/kg body weight intraperitoneally day

1-7, 8-15 and 18-22 of gestation. Pups delivered at full term were kept under observation till maturity

when they were randomly mated. Pregnant animals were given vasicine, 2.5 mg/kg body weight

intraperitoneally from day 1 to day 20 of gestation. All the pups were recorded and examined closely for

any grossly abnormal fetuses. Except for occasional pregnancy wastage seen at 2.5 mg/kg and a dose


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related but partial wastage at higher doses vasicine did not exhibit any teratogenic effects or any other

adverse effects in any of pups of the first or second generation.

Groups of mated rabbits were given vasicine, 1.25, 2.5 and 5 mg/kg body weight intraperitoneally day 9-

16, 16-23 and 23-30 of pregnancy. Control groups were given saline. Some animals in the two highest

dose groups aborted while the rest of the animals delivered normally on the due date. The pups did not

show any gross abnormalities. They were observed till they reached adult age and then they reproduced

normally. No abnormality was detected in the second generation of the treated animals.

Reproduction toxicityIn a screening study of antifertility activity of a number of medicinal plants, an extract of A. vasica leaves

was included. Various doses of the extract were fed to albino mice 7 days before and 14 days during

cohabitation and to female rats on the day spermatozoa were detected in the vaginal smear and then for 4

more days. No effects on the pregnancy were recorded after administration of A. vasica leaves extract

either in mice or in rats.

In an anti-implantation study, aqueous, benzene and 50% ethanol extracts of A. vasica leaves and acetone

and methanol extracts of bark and root were fed to mated rats (five to ten animals per group), on day 1-7 of

pregnancy. About half of the animals treated with about 100 mg/kg of different A. vasica extracts did not

show any implantation sites.

A.vasica aqueous extract was included and the results were separately published. The extract at 175 mg/kgwas given orally during day 5-10 or 0-9 of gestation to seven mated females. All the animals were

delivered by caesarian section on day 20. There was no foetus observed in the treated animals but 104

resorptions. 104 implantations and 104 corpora lutea. Corresponding numbers in the controls were eight

resorptions, 98 implantations and 98 corpora lutea. The time of exposure differs between the two

publications despite it being obvious formed all other data that the two publications deal with one and the

same publications.

The effects of A. vasica spissum leaf extract on early gestation were studied in two experiments in rats

given the extract orally day 1-9 of gestation. In the first experiment one group of five mated females was

given 325 mg/kg body weight of A. vasica dissolved in saline by a gastric cannula. Another group of five

animals served as control and was given saline. The animals were sacrificed on day 18 of gestation and the

outcome of the gestation recorded. There was no effect on the maternal body weight or any other

parameter recorded in the form of statistically significant differences between the treated and the controlanimals.

Studies in human beings

Vasicine has been tried in a preliminary human study being conducted for interruption of mid-trimester

pregnancy by intraamniotic instillation of the drug. Doses above 60 mg were given in 12 cases and all of

them aborted. In another preliminary report, which might include the cases reported in the above study, 62

cases with intraamniotic instillation of the drugs are reported. All cases given more than 60 mg aborted

after about 48h. Furthermore, in other studies it has been shown that vasicine is a very effective oxytocic

agent in human beings stopping post-partum hemorrhage. Clinical studies in which intravenous and

intramuscular administrations were shown to be less effective than intraamniotic administration.

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ADHATODA VASICA1